Mutant C3Hf B/HeN (C3Hf) and parental C3H/HeN mice show reciprocal skin graft rejection, generation of cytotoxic T-lymphocytes and bi-directional mixed lymphocyte responses. In addition, some chemically induced tumors of C3Hf mice show unique growth properties in that they are rapidly rejected by autologous C3Hf mice but grow progressively in ancestral C3H mice, possibly as a result of reversal of the mutation found in C3Hf mice. We propose to exploit this system in order to investigate the nature of T-cell recognition of MHC antigens and its role in the immune destruction of malignant cells. Specifically using a combination of immunochemical and immunobiological methodologies we will investigate the importance of the nature of MHC antigen presentation and aspects of their structure to the activation and subsequent proliferation of immunocompetent cells as well as the role of such activation in tumor rejection. A precise determination of the effects of the mutation in C3Hf mice on MHC antigens will be made. The ability of isolated MHC antigens alone or in various combinations, both in soluble form and incorporated into liposomes, to stimulate allogeneic and anti-tumor proliferative and cytotoxic responses will be evaluated. In addition, similar experiments will be performed with chemically and structurally modified MHC antigens in order to identify aspects of structure which are important to the activation of immunocompetent cells both in allogeneic and anti-tumor responses. Finally, an attempt will be made, using purifed H-2 antigens, to isolate a T-cell receptor relevant to both allogenic responses and the immune destruction of tumor cells. Information gathered from these experiments should help to elucidate the mechanisms involved in the generation of both allogenic and tumor responses. Knowledge of these aspects of the activation of immunocompetent cells should significantly facilitate efforts at intervention and modification of the immune response and in particular immunotherapeutic approaches to human malignancy.